Background: 

Lacosamide is a new antiepileptic drug used as an additive therapeutic option for the treatment of focal epilepsy. The enhancement of late sodium influx (I_NaL) is thought to be fundamental for the beneficial cerebral electrophysiological effect. Because of the known proarrhythmic effect of I_NaL-induction in the course of congenital and acquired  Long-QT syndrome and due to reported proarrhythmic effects of lacosamide, we investigated this in an established experimental isolated heart model of proarrhythmia.

Methods and results: 

26 hearts of New Zealand White rabbits were retrogradely perfused employing a Langendorff-setup. Eight catheters were placed endo- and epicardially, thereby recording monophasic action potentials. Hearts were paced at seven different cycle lengths (300-900ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD₉₀), QT intervals and dispersion of repolarization. In addition, burst pacing was utilized to assess ventricular vulnerability. Thereafter, bradycardic AV-blocked hearts were perfused with a hypokalemic solution to enhance the occurrence of triggered activity (early afterdepolarizations and torsade de pointes).

After generating baseline data, the hearts were assigned to two groups: In group 1, hearts were treated with 10 µM lacosamide. Thereafter, 50 µM lacosamide were infused. Group 2 was perfused with 100 µM sotalol followed by 50 µM lacosamide.

Sole lacosamide caused a shortening of ventricular APD and QT-interval whilst significant dispersion of repolarization was observed. The incidence of ventricular arrhythmias was slightly increased under lacosamide perfusion. Perfusion with sotalol led to a significant increase in APD and QT-interval. Furthermore, significant dispersion of repolarization occurred. As a result the inducibility and spontaneous occurrence of VT episodes increased significantly. Additional perfusion with lacosamide led to a further increase in APD, QT-interval and dispersion of repolarization. These changes were accompanied by a further raised arrhythmia susceptibility with a significantly increased number of VT episodes and the spontaneous onset of torsade de pointes tachycardias.

Conclusion:

(1) Lacosamide reveals a proarrhythmic potential mainly based on increased dispersion of repolarization. (2) In the setting of QT prolonging comedications the proarrhythmic potential of lacosamide is significantly increased. (3) Based on these data, the proarrhythmic potential of lacosamide should be considered in its use and close ECG monitoring seems mandatory, especially in patients with proarrhythmic comedications.